Antibiotic Resistance

Vocabulary:
- Antibiotic resistance
- Multi-drug resistance
- Efflux pump
- Inactivating enzymes
- Target mimicry
- Drug synergy
Characterization:
- Identify major methods by which microbes resist antimicrobial drugs.
- Outline methods by which resistance can be shared among microbes.
Testing for Resistance:
- Describe how to test for antibiotic susceptibility and Minimum Inhibitory Concentration (MIC).
Combination Drug Therapies:
- Outline the mechanisms by which combination therapies function against bacterial infections.
Reading Material: OpenStax Ch. 14.4-6

Overview of Resistance:
- Major forms of drug resistance observed in bacteria and fungi.
- Resistance mechanisms can often be transferred between species.
- Some of these mechanisms are also used by viruses.
- Notable mechanism: Inactivating enzymes.

Bacterial Inactivation of Drugs:
- Inactivation is often achieved through random mutations of existing enzymes into specialized forms.
- Inactivating enzymes can be excreted into the environment or transferred to other strains or species.
- Examples of inactivating enzymes:
  - β-lactamase: Cleaves β-lactam antibiotics.
  - Kanamycin acetylase: Modifies aminoglycosides.
Keeping Drugs Out of Cells:
- Mechanisms include:
- Blocked Uptake/Penetration: Often results from point mutations.
- Efflux Pumps: May arise from point mutations and then spread by horizontal gene transfer (HGT).
Target Modification:
- The normal enzyme target mutates, preventing drug binding.
- This mutated version can be exchanged between species.

Enzyme Overproduction:
- Mutations in promoter/operator sequences can lead to increased levels of enzymes.
- Excess enzymes can consume available drugs while retaining functionality.
Target Mimicry:
- This is the most recently discovered mechanism of resistance.
- Certain species produce "decoy" molecules which attract and trap drugs, keeping them away from real targets.

Kirby-Bauer Disk Diffusion Assay:
- Formally known as Antimicrobial Susceptibility Test (AST).
- Disk assays use pre-loaded disks with specific doses of antibiotics.
- Diameters of inhibition zones are measured against a calibrated table, providing an industry standard.
- Tests effectiveness against Gram-positive and/or Gram-negative bacteria.
Minimum Inhibitory Concentration (MIC):
- MIC is determined using dilution methods to find the lowest concentration that inhibits the isolate.
- Clinical practice recommends achieving serum concentration of 3-5 times the MIC.
- This approach helps in defining the therapeutic window and addressing limitations of the Kirby-Bauer method regarding drug potency.
Etest:
- The most commonly used clinical method for determining both MIC and drug susceptibility.
- Cost: $4-8 per test strip.

Mycobacterium tuberculosis:
- Multidrug-Resistant Tuberculosis (MDR-TB) is resistant to both rifampin and isoniazid.
- Extensively Drug-Resistant TB (XDR-TB) is MDR-TB with resistance to fluoroquinolones and another agent.
Staphylococcus aureus:
- Methicillin-Resistant Staphylococcus aureus (MRSA).
- Vancomycin-Resistant Staphylococcus aureus (VRSA) and Vancomycin-Intermediate Staphylococcus aureus (VISA).
Enterococci:
- Vancomycin-Resistant Enterococci (VRE), which can transfer resistance to MRSA.
Extended Spectrum β-lactamase (ESBL):
- Present in certain Gram-negative pathogens leading to resistance against penicillins, cephalosporins, and monobactams.
- Often harbors multi-drug resistance plasmids.
Carbapenem-Resistant Gram-negative pathogens (CRE):
- A major public health threat, highlighting the urgent need for monitoring and addressing resistance.

Threat Classification:
- Changes in rates or numbers of infections between 2019 and 2022 were identified.
- Notable trends:
- Hospital-onset CRE: Increased rates observed.
- Hospital-onset Carbapenem-resistant Acinetobacter: Increased.
- Clinical Cases of C. auris: Stable.
- Hospital-onset MRSA: Increased, stable in subsequent years but showed a decrease at one interval.
- Hospital-onset VRE: Increases noted.
- Hospital-onset ESBL-producing Enterobacterales: Increased in comparison.
- Hospital-onset MDR Pseudomonas aeruginosa: Increased rates observed.

Five D's:
- Right Drug
- Right Dose
- Right Delivery
- Suitable Duration
- De-escalation
Five R's:
- Responsibility
- Review (within 48 hours)
- Refine (treatment plan)
- Reduce (antibiotic usage)
- Replace (therapy as identified)
These principles aim to improve care quality and mitigate antimicrobial resistance.

Centers for Disease Control and Prevention (CDC) mission statement:
- “Saving Lives, Protecting People™”
Focus on:
- Antibiotic prescribing and use in healthcare settings.
- Core Elements of Antibiotic Stewardship to guide implementation.

Antibiotic Use Guidance:
- Key points on appropriate antibiotic use include:
- Only use antibiotics when necessary.
- Antibiotics are effective against bacterial infections but not viral infections.
- Incorrect use can lead to resistance and adverse effects.

Listeria monocytogenes:
- Current best practice for treatment involves high-dose ampicillin combined with gentamicin.
- This dual therapy minimizes the risk of resistance by targeting different bacterial pathways.
- Awareness of the ampicillin resistance in up to 40% of animal isolates is crucial as Listeria often originates from livestock.
Pseudomonas aeruginosa:
- No established best practice; isolates must be tested for resistance, which establishes their antibiotic resistance profile known as an "antibiogram".

Increasingly, antibiotics are prescribed in combination to achieve better therapeutic outcomes.
- This strategy targets multiple pathways, enhancing overall effectiveness against resistant strains.
- Non-antibiotic agents may also be included to disrupt resistance mechanisms.
Examples of Combination Antibiotic Therapies:
- Augmentin: Amoxicillin (3rd generation β-lactam, more resistant to β-lactamase) combined with clavulanic acid (β-lactamase inhibitor) in oral form.
- Primaxin: Imipenem (IV-only β-lactam) combined with cilastatin (prevents breakdown of imipenem in kidneys); effective for UTIs.
- Recarbrio: Combination of Primaxin and relebactam (lactamase inhibitor); administered IV only.
- Avycaz: Ceftazidime (cephalosporin) combined with avibactam (lactamase inhibitor) used for complicated intra-abdominal infections; IV only.
- Neosporin: A topical ointment containing neomycin (aminoglycoside), polymyxin B (anti-G- membrane), and bacitracin (anti-G+ use).
- Tazocin/Zosyn: Piperacillin (broad-spectrum β-lactam) combined with tazobactam (lactamase inhibitor); IV only, notably popular at York Hospital.